Inflammatory Bowel Disease (IBD) is a group of disorders encompassing Crohn's disease and ulcerative colitis. As such, IBD represents one of the most prevalent gastrointestinal diseases in the US, costing approximately $1.7 billion annually. Because IBD is incurable, patients are forced to endure repeated hospitalizations and surgeries. Moreover, since IBD disproportionately impacts people of low socio-economic status, the cost burden of IBD falls most heavily on those most susceptible to financial hardship. Extensive research into the genetics of IBD over the last several decades led to the development of several animal models for Crohn's disease and ulcerative colitis. By comparison, the study of environmental risk factors like diet has accelerated to equivalent levels only in the last few years. Indeed, while a Western diet low in fiber and high in fat has long been correlated with development of IBD, it was only recently shown that low dietary fiber exacerbates IBD. Studies of other dietary factors, including salt, remain to be performed. We specifically propose to examine the role of a high-salt diet (HSD). Recent studies show that dietary salt can exacerbate autoimmune encephalitis, suggesting that a HSD could contribute to other auto-immune diseases like inflammatory bowel disease (IBD). Indeed, in preliminary experiments, we have observed that animals on a HSD display exacerbated inflammation and increased inflammatory cytokine production in two models of murine colitis: the Il10-/- model of inflammatory colitis, and the S. typhimurium model of infectious colitis. Our data thus indicates that a HSD can exacerbate intestinal inflammation in mice. Based on these data, we propose to examine the role of the innate immune system in HSD- exacerbated colitis, as well as the involvement of the serum and glucocorticoid kinase (SGK1) which has previously been described as an osmosensor in Th17 cells. We specifically hypothesize that innate immune cells respond to dietary salt, increasing their inflammatory output in these models of colitis. To address this hypothesis, we will examine T cell deficient (Rag knockout) mice in both models, and compare histology, cytokine expression and cellular recruitment on a HSD vs a LSD. (AIM 1). We will also specifically examine the role of SGK1 in innate cells using a small molecule inhibitor, and genetic knockout mice. (AIM 2). The implications of this proposal are far reaching. In determining how dietary salt drives IBD, our research may suggest potential drug targets (e.g. signaling pathways responsible for enhanced immune activation), or prophylactic dietary guidelines (i.e. low-salt diets for people with IBD). The latter public health approach is particularly important, as dietary guidelines are inexpensive and can be implemented immediately to provide relief to those suffering with IBD.